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Objective Concurrent autoimmune disorders, including autoimmune hepatitis (AIH), with Graves disease have been reported. Glucocorticoids can simultaneously lower thyroid hormone levels and treat AIH. Recurrence of hyperthyroidism is associated with recurrence of hepatitis. We present a case of coexisting AIH and Graves thyrotoxicosis, which improved with prednisone, but the thyrotoxicosis recurred during a prednisone taper while the hepatitis stayed in remission. Methods Evaluation included measurements of liver enzyme levels, thyroid function tests, and thyroid-stimulating antibodies as well as abdominal ultrasound, magnetic resonance imaging, and liver biopsy. Results A 47-year-old woman presented with nausea and jaundice. Workup showed an aspartate aminotransferase level of 1956 (reference, 10-42) U/L and alanine aminotransferase level of 1634 (reference, 14-54) IU/L. The liver biopsy was consistent with AIH. Nine months later, she reported palpitations, heat intolerance, and weight loss and was diagnosed with Graves disease. The patient received prednisone at 60 mg daily, and the liver and thyroid functions normalized after 1 month. Prednisone was tapered to 5 mg daily. Seven months later, she presented with a thyroid-stimulating hormone level of 0.049 (reference, 0.340-5.6) μIU/mL) and free thyroxine level of 3.96 (reference, 0.58-1.64) ng/dL. Liver enzymes remained at normal levels. Prednisone was increased from 5 to 20 mg to treat hyperthyroidism. The patient was referred for thyroidectomy for a diagnosis of Graves disease with thyrotoxicosis. Conclusion This case is an example of coexisting autoimmune diseases, Graves disease and AIH, with different clinical courses. Despite initial resolution with glucocorticoid therapy, Graves disease recurred, while AIH stayed in remission.

Objective The objective of this report is to highlight the possible but little-known association between coronavirus disease 2019 (COVID-19) and delayed onset of central hypocortisolism, which may be of significant clinical importance. Methods We describe a patient who developed new-onset central hypocortisolism in the convalescent phase of mild COVID-19, which has not been previously reported. Results A 47-year-old man with recent COVID-19 upper respiratory tract infection developed new-onset persistent dyspepsia and eosinophilia for which multiple investigations were normal. He was eventually diagnosed with central hypocortisolism, as evidenced by 8 AM cortisol level of 19 nmol/L (normal, 133-537 nmol/L) and adrenocorticotropic hormone of 7.1 ng/mL (normal, 10.0-60.0 ng/mL). He was started on hydrocortisone, which led to resolution of both dyspepsia and eosinophilia. At the same time, an interesting thyroid function trend was observed—an initial increase in both free thyroxine and thyroid stimulating hormone was followed by temporary central hypothyroidism before subsequent spontaneous recovery. On follow-up 3 weeks later, the patient remained hypocortisolemic. Conclusion COVID-19 may be associated with the delayed onset of central hypocortisolism in its convalescent phase. Although various mechanisms are possible, hypothalamic-pituitary activation during systemic illness, followed by a rebound decrease in activity after recovery, is consistent with the clinical course and thyroid function trend in this patient. It is essential that physicians consider endocrinopathies in the differential diagnosis of such cases, given the risk of life-threatening adrenal crises and their possible contribution to persistent symptoms following recovery from COVID-19.

Objective Tyrosine-kinase inhibitors (TKIs) are chemotherapeutic agents associated with increased thyroid-hormone requirements and altered deiodinase activity. We present the first case to link these findings to the TKI ibrutinib. Methods Serial thyroid-stimulating hormone (TSH), free-thyroxine (FT4), free-triiodothyronine (FT3), and reverse-triiodothyronine (rT3) levels were assessed. Results An 80-year-old, 62-kg woman with hypothyroidism secondary to total thyroidectomy for stage I papillary thyroid cancer, on maintenance levothyroxine (LT4) 137 μg daily, presented for follow-up. Compared to one year prior, the patient’s weight had increased by 2 kg and TSH from 2.58 to 27.60 μIU/mL (normal: 0.45-4.50 μIU/mL) while on pantoprazole. Ibrutinib, her other medication, had been started seven months prior for chronic lymphocytic leukemia. Despite sequential confirmation of proper LT4 adherence and self-administration, adjustment of LT4 to 150 μg, and discontinuation of pantoprazole, the patient’s hypothyroid symptoms worsened, and the TSH was 73.90 μIU/mL six months later. LT4 was increased to 175 μg six days a week and 262.5 μg once weekly. Two months later, the TSH was 3.92 μIU/mL (steady-state condition), FT4 2.32 ng/dL (normal: 0.82-1.77 ng/dL), FT3 1.6 pg/mL (normal: 2.0-4.4 pg/mL), and rT3 69.6 ng/dL (normal: 9.2-24.1 ng/dL). Ibrutinib was discontinued the next month due to gastrointestinal side effects and elevated blood pressure. Four months later, LT4 had been reduced to 150 μg, and the FT4 reached 1.92 ng/dL, FT3 2.0 pg/mL, and rT3 26.6 ng/dL. Conclusion This report links ibrutinib to increased thyroid-hormone requirements in a thyroidectomized woman whose decreased T3:T4, T3:rT3, and T4:rT3 ratios suggested type 3 deiodinase induction and type 2 deiodinase inhibition.

Introduction and importance Pituitary apoplexy is defined as a sudden onset of neurologic deficit due to infarction or hemorrhage of the pituitary tumor. We report a case of emergency endoscopic surgery for pituitary apoplexy presenting as cerebral infarction due to ICA compression in a limited resources condition. Case presentation A 38-year-old female presented with acute onset of severe headache, decreased level of consciousness, decreased visual acuity bilaterally, aphasia, and right hemiparesis. Computed tomography angiography showed a hyperdense sellar mass with stenosis of the left ICA. The patient underwent emergent endoscopic transsphenoidal surgery for sellar decompression. Clinical discussion The epidermiology, presentation and diagnosis and strategy of treatments as well as their outcomes were discussed. Conclusion Pituitary apoplexy should be taken into consideration in a patient with increasing headache and neuro-ophthalmic symptoms. Pituitary apoplexy presenting as cerebral infarction is rare. The aim of surgery in emergency setting was sellar decompression. Endoscopic transsphenoidal surgery was an effective treatment., Highlights • Pituitary apoplexy should be taken into consideration in a patient with increasing headache and neuro-ophthalmic symptoms. • Pituitary apoplexy presenting as cerebral infarction is rare. • The aim of surgery in emergency setting was sellar decompression. • Endoscopic transsphenoidal surgery was an effective treatment.

Objective Precise risk stratification and triage of coronavirus disease 2019 (COVID-19) patients are essential in the setting of an overwhelming pandemic burden. Clinical observation has shown a somewhat high prevalence of sick euthyroid syndrome among patients with COVID-19. This study aimed to evaluate the predictive value of free triiodothyronine (FT3) at the clinical presentation of COVID-19 for disease severity and death. Methods This retrospective cohort study was based on electronic medical records. The study was conducted at Sheba Medical Centre, a tertiary hospital where several acute and chronic wards have been dedicated to the treatment of patients with COVID-19. The primary outcome measure was death during hospitalization; secondary outcomes included hospitalization in intensive care, mechanical ventilation, and length of hospitalization. Results Of a total of 577 polymerase chain reaction-positive patients with COVID-19 hospitalized between February 27 and July 30, 2020, 90 had at least 1 measurement of thyroid-stimulating hormone, free thyroxine, and FT3 within 3 days of presentation. After applying strict exclusion criteria, 54 patients were included in the study. Patients in the lowest tertile of FT3 had significantly higher rates of mortality (40%, 5.9%, and 5.9%, P = .008), mechanical ventilation (45%, 29.4%, and 0.0%; P = .007) and intensive care unit admission (55%, 29.4%, and 5.9%, P = .006). In multivariate analyses adjusted for age, Charlson comorbidity index, creatinine, albumin, and white blood cell count. FT3 remained a significant independent predictor of death. Conclusion FT3 levels can serve as a prognostic tool for disease severity in the early presentation of COVID-19.

Highlights • The effects of air pollution on the placental iodine load are scarcely studied. • PPM2.5 in the third trimester of pregnancy was inversely associated with the placental iodine load. • DLNMs estimated the week-specific associations between PM2.5 and the placental iodine load. • Iodine mediates the effect of gestational PM2.5 exposure on cord blood FT4., Background Adequate intake of iodine is required for the production of thyroid hormones and contributes in pregnant women to a healthy brain development and growth in their offspring. To date, some evidence exists that fine particulate air pollution is linked with the fetal thyroid hormone homeostasis. However, possible effects of air pollutants on the placental iodine storage have not been investigated so far. Objectives We investigated the association between air pollution exposure to particulate matter with a diameter less than 2.5 µm (PM2.5), NO2, and black carbon and the placental iodine load. Methods The current study is part of the ENVIRONAGE birth cohort and included 470 mother-newborn pairs. Iodine concentrations were measured in placental tissue. A high-resolution air pollution model was used to estimate the daily exposure to PM2.5, NO2, and black carbon over the entire pregnancy based on the maternal residential addresses. Distributed lag nonlinear models (DLNMs) were used to estimate gestational week-specific associations between placental iodine concentrations and the air pollutants to understand the impact of specific exposure windows. Results PM2.5 showed a positive association with placental iodine concentration between the 16th and 22nd week of gestation. In contrast, a significant inverse association between PM2.5 and placental iodine concentration was observed in gestational weeks 29–35. The effect estimate, for a 5 µg/m3 increment in PM2.5 concentration, was the strongest at week 32 (β −0.11 µg/kg; 95%CI: −0.18 to −0.03). No associations were observed between placental iodine concentrations and NO2 or black carbon. Assuming causality, we estimated that placental iodine mediated 26% (−0.33 pmol/L; 95%CI: −0.70 to 0.04 pmol/L) of the estimated effect of a 5 µg/m3 increment in PM2.5 exposure on cord blood free thyroxine (FT4) concentrations. Conclusion In utero exposure to particulate matter during the third trimester of pregnancy is linked with a lower placental iodine load. Furthermore, the effect of air pollution on cord blood FT4 levels was partially mediated by the placental iodine load.

Graphical abstract, Highlights • Toxicological evaluations of blk. 333 according to OECD guidelines were negative. • Blk. 333 was not mutagenic in vitro and showed no in vivo genotoxic activity. • The NOAEL of the 90-day study was 2000 mg/kg bw/d blk. 333—the highest dose tested. • No target organs or treatment-related toxicological effects were identified. • Our results are relevant to a safety assessment of human ingestion of blk. 333., Humic substances are ubiquitous in soils and waters. These complex superstructures are derived from the decomposition of dead plant and animal matter and are vital to soil health. Their heterogenous composition is specific to their site of origin and is comprised of weakly bound aggregates of small organic compounds that can sequester minerals and make them available to plants. As such, they may possess potential nutritional value for humans, and extractions of fulvic and humic acids can be produced that could be suitable for such purposes. For this reason, we evaluated the toxicological profile of a specific preparation (blk. 333) of fulvic and humic acids derived from a lignite deposit in Alberta, Canada and found it to lack genotoxic potential in a bacterial reverse mutation test, in vitro mammalian chromosomal aberration test, and in vivo mammalian micronucleus test. No general or organ toxicity was observed in Wistar rats following 90 days of continuous exposure, and a no observed adverse effect level (NOEAL) was determined at 2000 mg/kg bw/day, the highest tested dose. Our results suggest the feasibility of further evaluation for development of the preparation as a nutritional supplement in food.

Central hypothyroidism (CH) is a rare cause of hypothyroidism. CH is frequently overlooked, as its clinical picture is subtle and includes non-specific symptoms; furthermore, if measurement of TSH alone is used to screen for thyroid function, TSH concentrations can be normal or even above the upper normal reference limit. Indeed, certain patients are at risk of developing CH, such as those with a pituitary adenoma or hypophysitis, those who have been treated for a childhood malignancy, have suffered a head trauma, sub-arachnoid hemorrhage or meningitis, and those who are on drugs capable to reduce TSH secretion. Keywords: Hypopituitarism, Central hypothyroidism, Thyrotropin deficiency, Congenital hypothyroidism

Background: Measurement of serum thyroperoxidase autoantibodies (TPOAb) during gestation as a classical marker for the risk of postpartum thyroiditis (PPT) predicts PPT in 1/3 to 1/2 of women. Very few studies have measured serum thyroid hormone Ab (THAb) during gestation, and none as a possible marker for PPT. Methods: In 412 women who were followed up from 7 to 11 weeks of gestation through 12 months after delivery, we measured THAb (T3.IgM, T3.IgG, T4.IgM, T4.IgG), thyroglobulin autoantibodies (TgAb) and TPOAb at study entry (7–11 week of gestation). Results: Sixty-three women (15.3%) developed PPT, which progressed to permanent hypothyroidism (PH) in 34/63 (54%). THAb+ve were 21/412 women (5.1%), the frequency being greater in those who then developed PPT (12/63 [19.0%] vs. 9/349 [2.6%], P = 4.6 × 10−8), and in the PH subgroup (26.5% [9/34] vs. 10.3% [10/29], P = 0.12). THAb positivity occurred in 9/76 women (11.8%) who were TgAb and/or TPOAb+ve compared to 12/336 women who were TgAb and TPOAb negative (3.6%, P = 0.0031). Of these 9 THAb+ve, TgAb and/or TPOAb+ve women, all (100%) developed PPT compared to 3/11 (27.3%, P = 0.0011) THAb+ve, TgAb and/or TPOAb negative women. Of these 9 and 3 PPT women, 8 and 1 progressed to PH (88.9% and 33.3%, respectively, P = 0.12). Conclusions: Gestational positivity of THAb enhance enormously the predictivity for PPT of gestational positivity of TPOAb/TgAb. However, their low frequency (5.1%) and their sensitivity (17.5% [21/63]) go against their application in lieu of TPOAb/TgAb. Keywords: Thyroid autoimmunity, Thyroid hormone autoantibodies, Pregnancy, Postpartum, Postpartum thyroiditis

Background The measurement of free thyroid hormone, instead of the total form, is more commonly used in current practice. We aimed to evaluate the usefulness of the ratio of serum free triiodothyronine (FT3, pg/mL) to free thyroxine (FT4, ng/dL) for differentiating Graves' disease from subacute thyroiditis. Materials and methods Medical records of thyrotoxic patients aged >15 years who had measurement of FT3, FT4 and thyrotropin on the first diagnosis of thyrotoxicosis before initiating treatment were retrospectively reviewed. Data were collected from all clinics, and were not limited to the endocrine clinic. Pregnant women were excluded. Results A total of 548 patients (468 with Graves' disease, 40 with subacute thyroiditis and 40 with toxic adenoma/multinodular goiter) were recruited. Mean age was 43.9 ± 15.4 years. Most were female 434 (79.2%), and goiter was present in 55.3%. Prevalence of T3-toxicosis and T4-toxicosis were 5.6% and 6.6%, respectively. Mean FT3/FT4 ratios were 4.62 ± 2 (10−2 pg/ng) in patients with Graves' disease and 2.73 ± 0.5 in subacute thyroiditis. The area under the ROC curve of the FT3/FT4 ratio for diagnosis of Graves' disease was 0.83 (95%CI, 0.76–0.91). Cutoff level of this ratio >4.4 offered sensitivity of 47.2% and specificity of 92.8%. Conclusions FT3/FT4 ratio of >4.4 (10−2 pg/ng) may help in differentiating the cause of thyrotoxicosis., Highlights • The ideal treatment of thyrotoxicosis should be directed at its etiology. • Serum total triiodothyronine (T3): thyroxine (T4) ratio (ng/ug) of >20 suggests Graves' disease. • In the current practice, the measurement of free thyroid hormone is more commonly used. • Serum free T3/free T4 ratio of >4.4 (10−2 pg/ng) may help in differentiating the cause of thyrotoxicosis.

Background The aim of this retrospective observational study was to describe thyroid function parameters (fT3, fT4 and TSH) in the course of normal pregnancies. Methods Data were obtained between 2006 and 2007 at the University Hospital in Innsbruck, Austria. The starting point was the identification of women who had had a normal birth as recorded in the birth registry of Tyrol. Thyroid function parameters were determined using methods implemented at the Department of Nuclear Medicine in Innsbruck. Results The fT3 and fT4 values were normally distributed. Grouping the results by trimester revealed the following values: 4.93 ± 0.59, 4.54 ± 0.48, and 4.27 ± 0.45 pmol/l for fT3; and 15.23 ± 2.43, 13.79 ± 1.99, and 13.32 ± 0.2.01 pmol/l for fT4, respectively. The values corresponding to the 10th-percentile were 3.9 pmol/l for fT3 and 11.3 pmol/l for fT4, respectively. TSH values showed a typical left skewed distribution, thus the mean values were calculated after log transformation of the data. The corresponding mean trimestral values for TSH were 1.46 ± 1.29, 1.68 ± 1.23, and 1.70 ± 2.22 mIU/l, respectively. Conclusion In an iodine sufficient population, thyroid function parameters in normal pregnancies do not differ from those in non-pregnant women. Our previously defined reference range for TSH of 0.3 to 3.5 mIU/l is equally valid for normal pregnancies. General significance The question of cognition and IQ development of children has been proposed to be associated with thyroid function. The addition of data regarding normal thyroid function during pregnancy will contribute to this research., Highlights • TSH levels in normal pregnancies do not differ from levels seen in adults. • The 10th-percentile value for fT3 in pregnancy is 3.9 pmol/l. • The 10th-percentile value for fT4 in pregnancy is 11.3 pmol/l. • A drop of TSH levels early in pregnancy is not a general phenomenon.

Objective Plasma total adiponectin reveals a sexual dimorphism indicating that gonadal steroids may be involved in its secretion and/or metabolism. However, results from previous reports are conflicting and data regarding the influence of ovarian steroids on adiponectin's multimer forms are scarce. The objective of the study was to assess if total adiponectin and its isoforms are affected by the changes of estradiol and progesterone during the normal menstrual cycle and the association of total adiponectin and its isoforms with the gonadal steroid levels. Materials/methods Quantitative determination of plasma adiponectin and its multimers was conducted in the three phases of an ovulatory cycle in 13 premenopausal women, in the follicular phase of 10 more premenopausal women, in 20 postmenopausal women and in 21 men. Moreover, serum levels of FSH, LH, prolactin, estradiol, progesterone, and testosterone, sex hormone binding globulin, glucose, and insulin were measured. Results The circulating levels of total adiponectin and its multimers were not affected by the normal variation of estradiol and progesterone across the ovulatory menstrual cycle. In the whole number of participants, the total adiponectin and high molecular weight adiponectin levels were significantly different between genders and associated positively with age and sex hormone binding globulin levels, and negatively with testosterone and progesterone levels and the waist/hip ratio. In the multiple logistic regression analysis, after adjustment for age, gender, and sex hormone binding globulin and progesterone levels, significant predictors of total adiponectin levels were the waist/hip ratio and testosterone levels, and of high molecular weight adiponectin the testosterone levels. Conclusions Normal menstrual cycle ovarian steroids are not involved directly in the regulation of secretion and/or metabolism of total adiponectin and its multimers. Testosterone seems to be responsible for the adiponectin's sexual dimorphism., Highlights • Adiponectin and its multimers were assessed in the three-step hormonal model of normal menstrual cycle. • Estrogens may not be involved directly in the regulation of adiponectin's secretion and/or metabolism. • Androgens appear to be responsible for the sexual dimorphism of adiponectin.

Background The aim of this study was to investigate the influence of a combined supplementation with magnesium, selenium and coenzyme Q10 on the morphology of the thyroid in patients with benign diseases. The clinical examination and treatment approach aims additionally at treating musculoskeletal and psychological stress. Methods A group of 8 patients (5 with hyperthyroidism, 3 with hypothyroidism) who initially attended a public institution received additional treatment at our private institution. The basic pharmacological treatment, i.e. substitution or thyreostatic, was kept unchanged. The inclusion of patients required good quality ultrasound images to be available. Results Initially the changes of the musculoskeletal system were corrected. Following this, stress components were also treated. After a period of 2–4 years of supplementation we observed a normalization of thyroid morphology as evidenced on ultrasound while at the same time there was a reduction of perfusion intensity. Thyroid antibody titers decreased in the majority of cases. Failure of the treatment was seen in 2 cases of chronic thyroiditis that was present for more than 10 years. The ultrasound images of these patients suggest a possible fibrosis. Conclusions In spite of the limitation due to the small number of cases, our observational study has delivered proof of concept for our examination and treatment model for benign thyroid disease. General significance Our results challenge validity of the prevailing dogma of a destructive unstoppable “autoimmune” destructive process of the gland. At the same time it shows new therapeutic options for patients with thyroid disease., Highlights • Adequate magnesium levels in blood can be attained by long time supplementation. • Thyroid morphology in young patients with benign thyroid disease can improve with supplementation. • Additional supplementation with selenium and coenzyme Q10 is needed in some cases. • Our results challenge the validity of the dogma of thyroid autoimmunity as an immovable process.

Central hypothyroidism (CH) occurs approximately in 1:50,000, and therefore is expected to be one thousand times rarer compared with primary hypothyroidism. Despite its rarity in the general population, it is much more common in certain disorders, in which it is frequently associated with other pituitary hormone deficiencies. The aim of this paper is to provide an updated review on the frequency of congenital CH, which is

Aims: To analyze the correlation between neck circumference (NC) and non-alcoholic fatty liver disease (NAFLD) and compare the predictive value of NC for NAFLD with that of other simple anthropometric measures and other biochemical profiles. Methods: 2761 subjects, undergoing a medical check-up at the Changhai Hospital between October 01, 2012 and November 30, 2012, were recruited to the study. NC, other simple anthropometric measures, and biochemical profiles were analyzed. Results: NC in NAFLD subjects with or without elevated ALT were 38.94 ± 2.62 cm and 37.21 ± 3.06 cm respectively, which was significantly higher than that in subjects with other metabolic disorders (NC: 35.33 ± 3.03 cm) and in normal controls (NC: 32.60 ± 2.37) (both P

Highlights ► We used an ovine prenatal exposure model to a mixture of environmental chemicals. ► Male fetal thyroids of mixed exposure groups have reduced follicle counts. ► Fetal thyroids of animals in mixed exposure groups show increased proliferation. ► Thyroid glands of exposed fetuses showed regions with impaired differentiation. ► Fetal plasma levels of free thyroid hormones were normal., Ewes were exposed to sewage sludge-fertilized pastures in a study designed investigate pre-conceptual and/or gestational exposure to environmental chemicals. The in utero impact on fetal thyroid morphology and function at day 110 (of 145) of pregnancy was then determined. Pre-conceptual exposure increased the relative thyroid organ weights in male fetuses. The number of thyroid follicles in thyroids of fetuses after pre-conceptual or gestational exposure was reduced. This correlated with an increase in Ki67 positive cells. Pre-conceptual exposure to sewage sludge reduced small blood vessels in fetal thyroids. Thyroid tissues of exposed fetuses contained regions where mature angio-follicular units were reduced exhibiting decreased immunostaining for sodium-iodide symporter (NIS). Fetal plasma levels of fT3 and fT4 in exposed animals, however, were not different from controls suggesting compensatory changes in the thyroid gland to maintain homeostasis in exposed fetuses. The regional aberrations in thyroid morphology may impact on the post-natal life of the exposed offspring.

Background: It is well documented that overt hypothyroidism is associated with adverse pregnancy outcomes, but studies of subclinical hypothyroidism have demonstrated conflicting results. Objective: Thyroid hormones are known to regulate mitochondrial function, and the aim of this study was to examine the possible relationship of subclinical hypothyroidism and mitochondrial dysfunction to adverse pregnancy outcomes in pregnant women. Methods: Women in their third trimester of pregnancy (n = 113) who did not receive thyroid medication were included in this cross-sectional study. All participants were interviewed, and their thyroid status was determined. All participants had concentrations of thyroid hormones (fT 4 and tT 3) within the reference range. In addition to thyroid status, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were measured by flow cytometry. To establish a reference range of MMP and ROS, a group of euthyroid, nonpregnant women were used as euthyroid controls. Adverse pregnancy outcome was defined as preterm delivery, preeclampsia, placental abruption, Apgar score